Infantile spasms are an age-specific epileptic syndrome manifesting as clusters of spasms, impaired neurocognitive development, and often evolution to intractable epilepsy. The current treatment of infantile spasms is not always effective and is often associated with serious side effects. There is an urgent need to develop new effective therapies for this syndrome, as recognized recently in the NINDS-funded Curing Epilepsy meeting (2007). In this project, we plan to use a novel and only model of symptomatic infantile spasms in rats, to investigate the pathophysiology of this syndrome, identify biomarkers of therapeutic efficacy, upon which to screen new therapies. In preliminary studies, we have identified abnormalities in the physiology and function of the dopaminergic substantia nigra pars compacta neurons. Our specific aims are to determine whether these are ictal or interictal phenomena linked with the expression or predisposition to spasms and determine whether drugs that enhance the hyperpolarizing effects of GABAA receptors may increase the efficacy of existing GABAAergic antiepileptic drugs in suppressing the in vitro abnormalities associated with spasms as well as in treating spasms. To this end, we will use a combination of techniques, including stereotactic surgery and microinfusion of drugs, behavioral monitoring, in vivo and in vitro electrophysiology, histological and immunofluorescence methods of staining and confocal imaging, and gene expression analysis by quantitative RT-PCR. It is expected that at the conclusion of this study we will know whether the identified in vitro abnormalities are valid in vitro biomarkers for rapid screening of new therapies for infantile spasms. Furthermore, a potentially beneficial method of improving currently used antiepileptic drugs may be proven to-be beneficial in the treatment of infantile spasms. Lay Summary: Infantile spasms are an age-specific, difficult to treat, epileptic syndrome, often associated with neurodevelopmental impairments, especially in infants with pre-existing brain abnormalities (symptomatic infantile spasms). Given the urgency to identify new effective therapies, we plan to study a novel model of symptomatic infantile spasms, to identify and validate novel in vitro biomarkers of therapeutic efficacy, which will allow rapid screening of novel candidate therapies. We anticipate that the outcome of this study will provide new insights into the pathophysiology of the disease opening new avenues for effective treatments.